The search for chemical compounds potentially useful for cancer chemotherapy has led to isolation of a number of highly cytotoxic sesquiterpene lactones from plant sources over the past few years. Only a few of these lactones have also shown significant antitumor activity. This proposal describes a highly regioselective and stereoselective approach to the total synthesis of one class of these sesquiterpene lactones with demonstrated in vivo activity. The elemanolide sesquiterpene vernolepin has shown significant in vivo cytoxicity and in vivo tumor inhibitory activity. Vernolepin contains an alpha-methylene-delta-lactone, an alpha-methylene-gamma- lactone and a hydroxyl group adjacent to the CH2 of the gamma-lactone grouping as the functional groups believed to be responsible for the observed activity. It is the objective of the proposed research to develop an efficient total synthesis of vernolepin which will allow preparation of related natural derivatives and of modified analogs for pharmacological testing. A total synthesis of this class of lactones is of increased interest since some of the compounds related to vernolepin have not been available in sufficient quantities for in vivo testing. Application of the principles of synthetic analysis to vernolepin led to the selection of highly symmetrical and readily obtainable key intermediates for the synthesis of these highly functionalized sesquiterpenes. Specifically the use of bicyclo(4.3.1)decane intermediates provides a means for controlling stereochemistry and for facile introduction of the necessary functionality.